The objective of this proposal is to expand a family study of adolescent boys who experience severe substance dependence/abuse and conduct disorder. In this application we propose to evaluate an additional 200 patient probands (100 male probands and 100 female probands) and their families. An important strength of the controlled family study design proposed is that, in addition to the highly selected treatment families, we will also evaluate 200 control families, matched to the patient probands by gender, age, ethnicity, and zip code of residence. The oversampling of highly selected treatment families, in combination with unselected control families, provides a powerful analytical design for understanding the familial aggregation and transmission of substance use disorders (SUD) and comorbid psychopathology in the population. These new data will double the size of the original family study of 200 male probands and their families and 200 control families currently in progress, allowing us to move beyond descriptive models to the investigation of underlying mechanisms and mediating variables in SUD. The inclusion of female patient probands will provide an important addition to the original study, enabling us to address critical issues concerning the generalizability of findings to female populations. In addition, the current study has been designed to interface not only with the original study, but also with the adoption study (Research Component 3) and twin study (Research Component 4) components of this Center Grant. Use of the same core of assessment instruments across these components will provide data that can be used jointly in analyses to decompose familial influences into genetic effects and family environmental components. Further, comparisons among the population twin sample, the adoption study families, and the control families in the current study will provide valuable tests of the generalizability of results across three distinct behavioral genetic designs.